While Bishop of Pereira, Castrillón Hoyos was reported to have walked the streets at night to help feed abandoned children.[1] While many Latin American bishops refused to accept contributions from suspected drug lords, Castrillón Hoyos accepted donations for his diocesan charities, arguing that by accepting the funds, they would be diverted from funding crime and instead used to help the poor. He said that when accepting such donations, he had warned the donors personally that their donations "would not save their souls".[1] Castrillón Hoyos once disguised himself as a milkman to gain access to the home of drug lord Pablo Escobar, and after revealing himself, the bishop persuaded Escobar to confess his sins.[1][2] Castrillón Hoyos also served as Secretary General (1983–1987) and President (1987–1991) of the Latin American Episcopal Conference, where he opposed liberation theology, which many of his colleagues supported.

Following the death of John Paul II, Castrillón participated in the 2005 papal conclave and was himself considered papabile, a possible successor to the papacy. Pope Benedict XVI confirmed him as Prefect of the Congregation for the Clergy and President of the Pontifical Commission Ecclesia Dei.

On 31 October 2006, Castrillón resigned as head of the Congregation for the Clergy. On 13 September 2007 Castrillón served as a spokesperson for Pope Benedict's motu proprio, Summorum Pontificum.[3]

On 23 February 2007, Castrillón became Protodeacon, the senior Cardinal-Deacon, which he remained until 1 March 2008, when he was elevated to Cardinal-Priest.

In January 2009, while Castrillón still headed the Pontifical Commission, Pope Benedict lifted the excommunications several bishops of the Society of St. Pius X (SSPX), including Richard Williamson, who was later identified a Holocaust denier. In September Bishop Anders Arborelius of Stockholm alleged that the Holy See had prior knowledge of Williamson's extreme views, and his view was confirmed by the papal nuncio to Sweden Archbishop Emil Paul Tscherrig who said he had warned the Vatican. Castrillón said that it was a "calumny" to suggest he had been aware of William's views. He said that if anyone in the Vatican should have known about the matter, it was Cardinal Giovanni Battista Re, Prefect of the Congregation of Bishops, who had responsibility for overseeing Williamson.[5][6][7]

In 2002, Castrillón expressed his disapproval of the zero-tolerance policy of the U.S. bishops with respect to cases of sexual abuse. He said the bishops ignored such "fundamental principles of the Church" as forgiveness and conversion.[8]

In 2001, Castrillón congratulated French bishop Pierre Pican, Bishop of Bayeux, France, for not notifying the police about a priest who had engaged in sexual abuse of minors. The priest was later sentenced to 18 years in jail. Bishop Pican himself received a suspended three-month jail sentence for not denouncing the priest.[9] In the letter Castrillón described the relationship between a bishop and his priests as "not professional but a sacramental relationship which forges very special bonds of spiritual paternity" and continued "The bishop has other means of acting ... but a bishop cannot be required to make the denunciation himself. In all civilised legal systems it is acknowledged that close relations have the possibility of not testifying against a direct relative."[10] When Castrillón's letter to Pican became public in 2010, Vatican spokesman Federico Lombardi said it showed how important it was to centralize handling of Catholic sex abuse cases by clerics under the Congregation for the Doctrine of the Faith."[11]

In 1997, Castrillón and the bishops of Ireland were at odds over the proper treatment of priests accused of sexual abuse. Castrillón expressed reservations about proposals discussed by the bishops.[12] While indicating that his Congregation was still studying the question, Castrillón wrote that some of the Irish bishops' proposals "appear contrary to canonical discipline", which could lead to actions being overturned if an appeal were made to a higher level. Castrillón mentioned the proposed policy of mandatory reporting to the civil authorities.[12] According to a 2011 RTÉ documentary, Castrillón told the Irish bishops in 1999 to be "fathers to your priests, not policemen". The documentary's depiction of resistance the Irish bishops experienced from Castrillón put them in a more favorable light at a time when they, and especially Archbishop Desmond Connell, were the target of savage criticism.[13]